1. Field of the Invention
The present invention relates to novel phosphorothioate compounds and pharmaceutical preparations thereof which are useful in reducing the effects of ionizing radiation on animal cells.
2. Discussion of the Background
The events leading up to the end of World War II were punctuated by the dropping of two nuclear bombs on the cities of Hiroshima and Nagasaki. The death, suffering, and permanent damage inflicted on the residents revealed just how devastating the effects of ionizing radiation could be.
These events initiated a vigorous research program into radioprotective agents to minimize the effects of radiation. The most effective agent to emerge from these efforts was S-2-[3-aminopropylamino]ethylphosphorothioic acid (1, WR2721) (U.S. Pat. No. 3,892,824). EQU H.sub.2 N(CH.sub.2).sub.3 NHCH.sub.2 CH.sub.2 SPO.sub.3 H.sub.2 1
Compound 1, is believed to undergo in vitro hydrolysis by the action of phosphatase enzymes to yield compound 2 EQU H.sub.2 N(CH.sub.2).sub.3 NHCH.sub.2 CH.sub.2 SH 2
which is also known to be a radioprotective agent (T. R. Sweeney "A Survey of Compounds From the Antiradiation Drug Development Program of the U.S. Army Research and Development Command", Walter Reed Army Institute of Research, 1979).
Additional research has discovered that 2-(2.varies.-carbamidoethylamino)ethanethiol 3 also shows good radioprotective activity, comparable to that of compound 2 (F. I. Carroll and M. E. Wall, J. Pharm. Sci., 1970, 59, 1350). ##STR1##
The phosphorothioate derivative of compound 3has been prepared (4 WR6458) (U.S. Pat. No. 3,501,557) however the ##STR2## result was a more toxic compound and therefore could not be tested at dose levels comparable to compound 1. At doses lower than the toxic level, no radioprotective activity was observed (see T. R. Sweeney ibid.). It has also been reported that compound 4 is effective for reducing mucin viscosity when administered in dosage rates ranging from 1-100 mg/kg/day (U.S. Pat. No. 4,424,216).
While anti-radiation drug treatment began as an effort to improve the survivability of nuclear war, a more practical aspect of the these research programs is the development of treatments for protecting cancer radiation therapy recipients. Clinical radiotherapy of malignant tumors unavoidably subjects adjacent healthy tissue to damaging radiation. It is desirable to chemically protect normal tissue from radiation injury without adversely affecting the radiosensitivity of the tumor. Even though both malignant and healthy tissue show comparable uptake of the radioprotective agent WR2721, the deficient vascular network of solid tumors reduces the uptake of the radioprotective agent. This partitioning allows for greater effectiveness in radiation treatment. The partitioning effect can be magnified by increasing the uptake of agents in healthy tissue or decreasing the uptake in tumor cells.
There remains a search for radioprotective agents with improved bioavailability and an increased partition coefficient.